Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis

Abstract

Atopic dermatitis (AD), a pruritic, inflammatory chronic disease with multifactorial pathogenesis, has been a therapeutic challenge. Novel target treatments aim to reduce not only the immunologic dysfunction and microbiome dysbiosis but also the recovery of the damaged skin barrier. The current review focuses on the interleukin 31 (IL-31) pathway and AD and offers an overview of the current clinical studies with monoclonal antibodies blocking this cascade. Pruritus, the key symptom of AD, has substantial participation of the IL-31 complex and activation of relevant signaling pathways. Epidermal keratinocytes, inflammatory cells, and cutaneous peripheral nerves express the interleukin-31 receptor α-chain (IL-31RA), upregulated by Staphylococcus aureus toxins or Th2 cytokines involved in AD. Nemolizumab is a humanized monoclonal antibody that antagonizes IL-31RA, inhibiting the IL-31 cascade and therefore contributing to reducing the pruritus and inflammation and recovering the damaged skin barrier in AD patients. Phases 2 and 3 clinical trials with nemolizumab in AD show a suitable safety profile, with a fast, efficient, and sustained reduction of pruritus and severity scores, especially when associated with topical treatment. Deciphering the full interplay of the IL-31 pathway and AD may expand the potential of nemolizumab as a targeted therapy for AD and other pruritic conditions.

Keywords: atopic dermatitis; interleukin-31 (IL-31); interleukin-31 receptor α-chain (IL-31RA); pruritus.

Figure 1

IL-31 role in AD skin inflammation. IL-31 is secreted by many cell types, such as Th2 cells, B cells, monocytes, macrophages, keratinocytes, fibroblasts, dendritic cells, eosinophils, basophils, and cutaneous peripheral nerves, with neuroimmune implications. It induces epidermal cell proliferation and thickening in the chronic Th1-mediated phase, increasing lichenification. Exposure to Staphylococcal exotoxins increases IL-31 release in macrophages and keratinocytes. After binding to its receptor, IL-31RA, and to OSMRβ heterodimer, it initiates an inflammatory cascade via phosphorylation of JAK/STAT, PI3K/AKT, and MAPK-JNK/p38 activation pathway, indicating a circle of itch–scratch–inflammation in AD skin. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 2

Timeline of clinical trials with Nemolizumab. Graphic timeline illustration of clinical trials involving nemolizumab both in adult and pediatric populations, described as: clinical trial number ID, sponsor, and current situation of the study, updated in 5 January 2023 according to https://clinicaltrials.gov (accessed on 5 January 2023) [60], https://www.clinicaltrialsregister.eu/ctr-search/search/ (accessed on 5 January 2023) [61], and https://rctportal.niph.go.jp (accessed on 5 January 2023) [62] websites. U.S.: United States; EudraCT: European Union Drug Regulating Authorities Clinical Trials Database; JAPIC: Japan Pharmaceutical Information Center.